The present invention relates to novel hydroxamate inhibitors of endothelin converting enzyme useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. More particularly, the novel compounds of the present invention are inhibitors of endothelin converting enzyme useful in treating elevated levels of endothelin and in controlling hypertension, myocardial infarction, metabolic, endocrinological, and neurological disorders, congestire heart failure, endotoxic and hemorrhagic shock, septic shock, subarachnoid hemorrhage, arrhythmias, asthma, acute and chronic renal failure, cyclosporin-A induced nephrotoxicity, restenosis, angina, ischemic disease, gastric mucosal damage, ischemic bowel disease, cancer, pulmonary hypertension, preeclampsia, atherosclerotic disorders including Raynaud's disease, cerebral vasospasm, and diabetes.
Endothelin-1 (ET-1), a potent vasoconstrictor, is a 21 amino acid bicyclic peptide that was first isolated from cultured porcine aortic endothelial cells. Endothelin-1, is one of a family of structurally similar bicyclic peptides which include; ET-2, ET-3, vasoactive intestinal contractor (VIC), and the sarafotoxins (SRTXs). The unique bicyclic structure and corresponding arrangement of the disulfide bridges of ET-1, which are the same for the endothelins, VIC, and the sarafotoxins, has led to significant speculation as to the importance of the resulting induced secondary structure to receptor binding and functional activity. ET-1 analogs with incorrect disulfide pairings exhibit at least 100-fold less vasoconstrictor activity.
Endothelin-1 is generated from a 203 amino acid peptide known as preproendothelin by an unknown dibasic endopeptidase. This enzyme cleaves the prepropeptide to a 38 (human) or 39 (porcine) amino acid peptide known as big endothelin or proendothelin. Big ET is then cleaved by an enzyme, known as endothelin converting enzyme or ECE, to afford the biologically active molecule ET-1. Big ET is only 1% as potent as ET-1 in inducing contractile activity in vascular strips but it is equally potent in vivo at raising blood pressure, presumably by rapid conversion to ET-1 (Kimura S, Kasuya Y, Sawamura T, et al, "Conversion of big endothelin-1 to 21-residue endothelin-1 is essential for expression of full vasoconstrictor activity: Structure-activity relationship of big endothelin-1," J. Cardiovasc Pharmacol 1989;13:S5). There have been numerous reports describing possible proteases in both the cytoplasm and membrane bound cellular fractions of endothelial cells (Ikegawa R, Matsumura Y, Takaoka M, et al, "Evidence for pepstatin-sensitive conversion of porcine big endothelin-1 to endothelin-1 by the endothelial cell extract," Biochem Biophys Res Commun 1990;167:860; Sawamura T, Kimura S, Shinmi O, et al, "Characterization of endothelin converting enzyme activities in soluble fraction of bovine cultured endothelial cells," Biochem Biophys Res Commun 1990;169:1138; Sawamura T, Shinmi O, Kishi N, et al, "Analysis of big endothelin-1 digestion by cathepsin D." Biochem Biophys Res Commun 1990;172:883; Shields P P, Gonzales T A, Charles D, et al, "Accumulation of pepstatin in cultured endothelial cells and its effect on endothelin processing," Biochem Biophys Res Commun 1991;177:1006; Matsumura Y, Ikegawa R, Tsukahara Y, et al, "Conversion of big endothelin-1 to endothelin-1 by two types of metalloproteinases derived from porcine aortic endothelial cells," FEBS Lett, 1990;272:166; Sawamura T, Kasuya Y, Matsushita S N, et al, "Phosphoramidon inhibits the intracellular conversion of big endothelin-1 to endothelin-1 in cultured endothelial cells," Biochem Biophys Res Commun 1991;174:779; Takada J, Okada K, Ikenaga T, et al, "Phosphoramidon-sensitive endothelin-converting enzyme in the cytosol of cultured bovine endothelial cells," Biochem Biophys Res Commun 1991;176:860; Ahn K, Beningo K, Olds G, Hupe D, "Endothelin-converting enzyme from bovine and human endothelial cells," J Vasc Res 1991;29:76, 2nd International symposium on endothelium-derived vasoactive factors). Many groups have chosen to isolate ECE from endothelial cells of various species, since endothelin is known to be synthesized and secreted by this cell type. It was initially reported that two types of protease activity were present in porcine or bovine endothelial cells that could cause conversion of big ET to ET in vitro (Ikegawa R, supra; Sawamura T, supra; Matsumura Y, supra; Takada J, supra; Ahn K, supra). However, it was subsequently found that the aspartic protease activity from porcine endothelial cells, thought to be predominantly cathepsin D, also caused further degradation of ET-1 and was therefore unlikely to be the true ECE (Sawamura T, supra). Moreover, human cathepsin D also causes rapid degradation of ET-1. In addition, there has been one study showing that the intracellular accumulation of pepstatin, an aspartic protease inhibitor, did not inhibit ET-1 production in cultured bovine aortic endothelial cells (Shields P P, supra). Stronger evidence that ECE is in fact a neutral metalloprotease has appeared (Matsumura Y, supra; Sawarnura T, supra; Takada J, supra; Ahn K, supra), although to date there have been no known specific metalloprotease ECE inhibitors to confirm these findings in vivo. However, the nonspecific metalloproteinase inhibitor, phosphoramidon, has been shown to inhibit the intracellular conversion of big ET-1 to ET-1 in cultured vascular endothelial cells and smooth muscle cells (Sawamura T, supra).
ET-converting activity has been detected in both the membranous and cytosolic fractions of cultured porcine, bovine, and human endothelial cells (Matsumura Y, supra). Micromolar concentrations of phosphoramidon have been shown to block the pressor response of big ET both in vitro and in vivo (Takada J, supra; Fukuroda T, Noguchi K, Tsuchida S, et al, "Inhibition of biological actions of big endothelin-1 by phosphoramidon," Biochem Biophys Res Commun 1990;172:390; Matsumura Y, Hisaki K, Takaoka M, Morimoto S, "Phosphoramidon, a metalloproteinase inhibitor, suppresses the hypertensive effect of big endothelin-1," Eur J Pharmacol 1990;185:103; McMahon E G, Palomo M A, Moore W M, et al, "Phosphoramidon blocks the pressor activity of porcine big endothelin-1-(1-39) in vivo and conversion of big endothelin-1-(1-39) to endothelin-1-(1-21) in vitro," Proc Natl Acad Sci USA 1991;88:703). It has recently been reported that phosphoramidon is able to inhibit vasoconstrictor effects evokedby intravenous injections of big ET-1 in anaesthetized pigs, but did not have any effect on the plasma ET-1 level (Modin A, Pernow J, Lundberg J M, "Phosphoramidon inhibits the vasoconstrictor effects evoked bybig endothelin-1 but not the elevation of plasma endothelin-1 in vivo," Life Sci 1991;49:1619). It should be noted that phosphoramidon is a rather general metalloproteinase inhibitor and clearly the discovery of specific ECE inhibitors such as those described in the present invention is important.
Endothelin is involved in many human disease states.
Several in vivo studies with ET antibodies have been reported in disease models. Left coronary artery ligation and reperfusion to induce myocardial infarction in the rat heart, caused a four- to seven-fold increase in endogenous endothelin levels. Administration of ET antibody was reported to reduce the size of the infarction in a dose-dependent manner (Watanabe T, et al, "Endothelin in Myocardial Infarction," Nature (Lond.) 1990;344:114). Thus, ET may be involved in the pathogenesis of congestire heart failure and myocardial ischemia (Marguiles K B, et al, "Increased Endothelin in Experimental Heart Failure," Circulation 1990;82:2226).
Studies by Kon and colleagues using anti-ET antibodies in an ischemic kidney model, to deactivate endogenous ET, indicated the peptide's involvement in acute renal ischemic injury (Kon V, et al, "Glomerular Actions of Endothelin In Vivo," J Clin Invest 1989;83:1762). In isolated kidneys, preexposed to specific antiendothelin antibody and then challenged with cyclosporine, the renal perfusate flow and glomerular filtration rate increased, while renal resistance decreased as compared with isolated kidneys preexposed to a nonimmunized rabbit serum. The effectiveness and specificity of the anti-ET antibody were confirmed by its capacity to prevent renal deterioration caused by a single bolus dose (150 pmol) of synthetic ET, but not by infusion of angiotensin II, norepinephrine, or the thromboxane A.sub.2 mimetic U-46619 in isolated kidneys (Perico N, et al, "Endothelin Mediates the Renal Vasoconstriction Induced by Cyclosporine in the Rat," J Am Soc Nephrol 1990;1:76).
Others have reported inhibition of ET-1 or ET-2-induced vasoconstriction in rat isolated thoracic aorta using a monoclonal antibody to ET-1 (Koshi T, et al, "Inhibition of Endothelin (ET)-1 and ET-2-Induced Vasoconstriction by Anti-ET-1 Monoclonal Antibody," Chem Pharm Bull 1991;39:1295).
Combined administration of ET-1 and ET-1 antibody to rabbits showed significant inhibition of the blood pressure and renal blood flow responses (Miyamori I, et al, Systemic and Regional Effects of Endothelin in Rabbits: Effects of Endothelin Antibody," Clin Exp Pharmacol Physiol 1990;17:691).
Other investigators have reported that infusion of ET-specific antibodies into spontaneously hypertensive rats (SHR) decreased mean arterial pressure (MAP), and increased glomerular filtration rate and renal blood flow. In the control study with normotensive Wistar-Kyoto rats (WKY), there were no significant changes in these parameters (Ohno A, "Effects of Endothelin-Specific Antibodies and Endothelin in Spontaneously Hypertensive Rats," J Tokyo Women's Med Coll 1991;61:951).
In addition, elevated levels of endothelin have been reported in several disease states (see Table I below).
TABLE I ______________________________________ Plasma Concentrations of ET-1 in Humans ET Plasma Normal Levels Reported Condition Condition (pg/mL) ______________________________________ Atherosclerosis 1.4 3.1 pmol/L Surgical operation 1.5 7.3 Buerger's disease 1.6 4.8 Takayasu's arteries 1.6 5.3 Cardiogenic shock 0.3 3.7 Congestive heart failure (CHF) 9.7 20.4 Mild CHF 7.1 11.1 Severe CHF 7.1 13.8 Dilated cardiomyopathy 1.6 7.1 Preeclampsia 10.4 pmol/L 22.6 pmol/L Pulmonary hypertension 1.45 3.5 Acute myocardial infarction 1.5 3.3 (several reports) 6.0 11.0 0.76 4.95 0.50 3.8 Subarachnoid hemorrhage 0.4 2.2 Crohn's disease 0-24 Fmol/mg 4-64 Fmol/mg Ulcerative colitis 0-24 Fmol/mg 20-50 Fmol/mg Cold pressor test 1.2 8.4 Raynaud's phenomenon 1.7 5.3 Raynaud's/hand cooling 2.8 5.0 Hemodialysis &lt;7 10.9 (several reports) 1.88 4.59 Chronic renal failure 1.88 10.1 Acute renal failure 1.5 10.4 Uremia before hemodialysis 0.96 1.49 Uremia after hemodialysis 0.96 2.19 Essential hypertension 18.5 33.9 Sepsis syndrome 6.1 19.9 Postoperative cardiac 6.1 11.9 Inflammatory arthritides 1.5 4.2 Malignant 4.3 16.2 hemangioendothelioma (after removal) ______________________________________
Burnett and co-workers recently demonstrated that exogenous infusion of ET (2.5 ng/kg/mL) to anesthetized dogs, producing a doubling of the circulating concentration, did have biological actions (Lerman A, et al, "Endothelin Has Biological Actions at Pathophysiological Concentrations," Circulation 1991;83:1808). Thus heart rate and cardiac output decreased in association with increased renal and systemic vascular resistances and antinatriuresis. These studies support a role for endothelin in the regulation of cardiovascular, renal, and endocrine function.
In the anesthetized dog with congestive heart failure, a significant two- to three-fold elevation of circulating ET levels has been reported (Cavero P G, et al, "Endothelin in Experimental Congestive Heart Failure in the Anesthetized Dog," Am J Physiol 1990;259:F312), and studies in humans have shown similar increases (Rodeheffer R J, et al, "Circulating Plasma Endothelin Correlates With the Severity of Congestire Heart Failure in Humans," Am J Hypertension 1991;4:9A). When ET was chronically infused into male rats, to determine whether a long-term increase in circulating ET levels would cause a sustained elevation in mean arterial blood pressure, significant, sustained, and dose-dependent increases in mean arterial blood pressure were observed. Similar results were observed with ET-3 although larger doses were required (Mortenson L H, et al, "Chronic Hypertension Produced by Infusion of Endothelin in Rats," Hypertension 1990;15:729). Recently the nonpeptide endothelin antagonist RO 46-2005 has been reported to be effective in models of acute renal ischemia and subarachnoid hemorrhage in rats (3rd International Conference on Endothelin, Houston, Tex., February 1993). In addition, the ET.sub.A antagonist BQ-153 has also been shown to prevent early cerebral vasospasm following subarachnoid hemorrhage after intracisternal injection (Clozel M, et al, Life Sciences 1993;52:825); to prevent blood pressure increases in stroke-prone spontaneously hypertensive rats (Nishikibe M, et al, Life Sciences 1993;52:717); and to attenuate the renal vascular effects of ET-1 in anaesthetized pigs (Cirino M, et al, J Pharm Pharmacol 1992;44:782).
The distribution of the two cloned receptor subtypes, termed ET.sub.A and ET.sub.B, have been studied extensively (Arai H, et al, Nature 1990;348:730; Sakurai T, et al, Nature 1990;348:732). The ET.sub.A, or vascular smooth muscle receptor, is widely distributed in cardiovascular tissues and in certain regions of the brain (Lin HY, et al, Proc Natl Acad Sci 1991;88:3185). The ET.sub.B receptor, originally cloned from rat lung, has been found in rat cerebellum and in endothelial cells, although it is not known if the ET.sub.B receptors are the same from these sources. The human ET receptor subtypes have been cloned and expressed (Sakamoto A, et al, Biochem Biophys Res Chem 1991;178:656; Hosoda K, et al, FEBS Lett 1991;287:23). The ET.sub.A receptor clearly mediates vasoconstriction and there have been a few reports implicating the ET.sub.B receptor in the initial vasodilatory response to ET (Takayanagi R, et al, FEBS Lett 1991;282:103). However, recent data has shown that the ET.sub.B receptor can also mediate vasoconstriction in some tissue beds (Panek R L, et al, Biochem Biophys Res Commun 1992;183(2):566).
Plasma endothelin-1 levels were dramatically increased in a patient with malignant hemangio-endothelioma (Nakagawa K, et al, Nippon Hifuka Gakkai Zasshi 1990;100:1453).
The ET receptor antagonist BQ-123 has been shown to block ET-1-induced bronchoconstriction and tracheal smooth muscle contraction in allergic sheep providing evidence for expected efficacy in bronchopulmonary diseases such as asthma (Noguchi, et al, Am Rev Respir Dis 1992;145(4 Part 2):A858).
Circulating endothelin levels are elevated in women with preeclampsia and correlate closely with serum uric acid levels and measures of renal dysfunction. These observations indicate a role for ET in renal constriction in preeclampsia (Clark B A, et al, Am J Obstet Gynecol 1992;166:962).
Plasma immunoreactive endothelin-1 concentrations are elevated in patients with sepsis and correlate with the degree of illness and depression of cardiac output (Pittett J, et al, Ann Surg 1991;213(3):261).
In addition, the ET-1 antagonist BQ-123 has been evaluated in a mouse model of endotoxic shock. This ET.sub.A antagonist significantly increased the survival rate in this model (Toshiaki M, et al, 20.12.90. EP 0 436 189 A1).
Endothelin is a potent agonist in the liver eliciting both sustained vasoconstriction of the hepatic vasculature and a significant increase in hepatic glucose output (Gandhi C B, et al, J of Biolog Chem 1990;265(29):17432).In streptozotocin-diabetic rats, there is an increased sensitivity to endothelin-1 (Tammesild P J, et al, Clin Exp Pharmacol Physiol 1992;19(4):261). In addition, increased levels of plasma ET-1 have been observed in microalbuminuric insulin-dependent diabetes mellitus patients indicating a role for ET in endocrine disorders such as diabetes (Collier A, et al, Diabetes Care 1992;15(8):1038).
ET.sub.A antagonist receptor blockade has been found to produce an antihypertensive effect in normal to low renin models of hypertension with a time course similar to the inhibition of ET-1 pressor responses (Basil M K, et al, J Hypertension 1992;10(Suppl 4):S49). The endothelins have been shown to be arrhythmogenic, and to have positive chronotropic and inotropic effects, thus ET receptor blockade would be expected to be useful in arrhythmia and other cardiovascular disorders (Hah S-P, et al, Life Sci 1990;46:767).
The widespread localization of the endothelins and their receptors in the central nervous system and cerebrovascular circulation has been described (Nikolov R K, et al, Drugs of Today 1992;28(5):303). Intracerebroventricular administration of ET-1 in rats has been shown to evoke several behavioral effects. These factors strongly suggest a role for the ETs in neurological disorders. The potent vasoconstrictor action of ETs on isolated cerebral arterioles suggests the importance of these peptides in the regulation of cerebrovascular tone. Increased ET levels have been reported in some CNS disorders, ie, in the CSF of patients with subarachnoid hemorrhage and in the plasma of women with preeclampsia. Stimulation with ET-3 under conditions of hypoglycemia have been shown to accelerate the development of striatal damage as a result of an influx of extracellular calcium. Circulating or locally produced ET has been suggested to contribute to regulation of brain fluid balance through effects on the choroid plexus and CSF production. ET-1-induced lesion development in a new model of local ischemia in the brain has been described.
Circulating and tissue endothelin immunoreactivity is increased more than two-fold in patients with advanced atherosclerosis (Lerman A, et al, New England J Med 1991;325:997). Increased endothelin immunoreactivity has also been associated with Buerger's disease (Kanno K, et al, J Amer Med Assoc 1990;264 2868) and Raynaud's phenomenon (Zamora M R, et al, Lancet 1990;336:1144). Likewise, increased endothelin concentrations were observed in hyper-cholesterolemic rats (Horio T, et al, Atherosclerosis 1991;89:239).
An increase of circulating endothelin levels was observed in patients that underwent percutaneous transluminal coronary angioplasty (PTCA) (Tahara A, et al, Metab Clin Exp 1991;40:1235; Sanjay K, et al, Circulation 1991;84(Suppl. 4):726).
Increased plasma levels of endothelin have been measured in rats (Stelzner T J, et al, Am J Physiol 1992;262:L614) and humans (Miyauchi T, et al, Jpn J Pharmacol 1992;58:279P; Stewart D J, et al, Ann Internal Medicine 1991;114:464) with pulmonary hypertension.
Elevated levels of endothelin have also been measured in patients suffering from ischemic heart disease (Yasuda M, et al, Amer Heart J 1990;119:801; Ray S G, et al, Br Heart J 1992;67:383) and either stable or Unstable angina (Stewart J T, et al, Br Heart J 1991;66:7).
Infusion of an endothelin antibody 1 hour prior to and 1 hour after a 60-minute period of renal ischaemia resulted in changes in renal function versus control. In addition, an increase in glomerular platelet-activating factor was attributed to endothelin (Lopez-Farre A, et al, J Physiology 1991;444:513-). In patients with chronic renal failure as well as in patients on regular hemodialysis treatment mean plasma endothelin levels were significantly increased (Stockenhuber F, et al, Clin Sci (Lond.) 1992;82:255). In addition, it has been suggested that the proliferative effect of endothelin on mesangial cells may be a contributing factor in chronic renal failure (Schultz P J, J Lab Clin Med 1992;119:448).
Local intra-arterial administration of endothelin has been shown to induce small intestinal mucosal damage in rats in a dose-dependent manner (Mirua S, et al, Digestion 1991;48:163). Administration of endothelin-1 in the range of 50-500 pmol/kg into the left gastric artery increased the tissue type plasminogen activator release and platelet activating formation and induced gastric mucosal hemorrhagic change in a dose-dependent manner (Kurose I, et al, Gut 1992;33:868). Furthermore, it has been shown that an anti-ET-1 antibody reduced ethanol-induced vasoconstriction in a concentration-dependent manner (Masuda E, et al, Am J Physiol 1992;262:G785). Elevated endothelin levels have been observed in patients suffering from Crohn's disease and ulcerative coliris (Murch S R, et al, Lancet 1992;339:381).
Japanese Published Patent Application JP 04041430-A, published Feb. 12, 1992, disclosed phosphoramidon as an endothelin converting enzyme inhibitor.
PCT International Published Patent Application WO 92/12170, published Jul. 23, 1992, discloses peptides of up to 20 amino acids including pentapeptides of the formula: EQU A.sub.3 --A.sub.4 --A.sub.5 --A.sub.4.sup.1 -A.sub.3.sup.1 (SEQ ID NO: 1)
wherein A.sub.3 and A.sub.3.sup.1 independently represent Ser, Gly, Asp, or Asn and A.sub.4 and A.sub.4.sup.1 independently represent Val, Pro, Gly, or Ala and A.sub.5 represents Asp or Asn. The peptides are disclosed to be inhibitors of endothelin formation.
PCT International Published Patent Application WO 92/01468, published Feb. 16, 1992, discloses compounds of the formula: ##STR1## wherein A.sub.1, A.sub.2 is an amino acid;
X is OH or a monosaccharide residue;
R.sub.1 is OH, alkyl, alkoxy, allyl, or NR.sub.2 R.sub.3,
wherein R.sub.2, R.sub.3 is H or alkyl. PA1 n is an integer of one to ten or ##STR11## wherein R.sup.5 is hydrogen or alkyl, and n is as defined above; ##STR12## wherein R.sup.6 is hydrogen or methyl, R.sup.7 is aryl or heteroaryl, and PA1 p is zero or an integer of one to four or PA1 AA.sup.1 is absent; ##STR13## wherein R.sup.8 is hydrogen, alkyl, alkenyl, or cycloalkyl, and R.sup.6 and p are as defined above or PA1 AA.sup.2 is absent; ##STR14## wherein R.sup.9 is hydrogen, ##STR15## wherein R.sup.10 and R.sup.11 are each independently the same or different and each is hydrogen, alkyl, cycloalkyl or --(CH.sub.2).sub.q -aryl, wherein q is zero or an integer of one or two or ##STR16## wherein R.sup.10 is as defined above and R.sup.6 and p are as defined above or PA1 AA.sup.3 is absent; PA1 AA.sup.4 and AA.sup.5 are each independently ##STR17## wherein R.sup.11 is hydrogen, alkyl, alkenyl, or cycloalkyl, and R.sup.6 and p are as defined above or one of PA1 AA.sup.4 or AA.sup.5 is absent; ##STR18## wherein R.sup.6, R.sup.7, and p are as defined above; R.sup.1 is hydrogen or alkyl; PA1 R.sup.2 is hydrogen, arylalkyl or alkyl; PA1 the stereochemistry at *C in AA.sup.1, AA.sup.2, AA.sup.3, AA.sup.4, AA.sup.5, or AA.sup.6 is L, D, or DL; or a pharmaceutically acceptable salt thereof.
The compounds are disclosed as agents for inhibiting endothelin converting enzyme.
PCT International Published Patent Application WO 92/13545, published Aug. 20, 1992, discloses compounds of the formula (these compounds also are described in Shiosaki K, et al, Journal of Medicinal Chemistry 1993;36:468): ##STR2## wherein A is hydrogen, an N-protecting group or R.sub.1 NHCH(R.sub.2)C(O)-- wherein R.sub.1 is H or an N-protecting group and R.sub.2 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, carboxyalkyl, or alkoxycarbonylalkyl; or A is HO.sub.2 C(CH.sub.2).sub.n C(O)-- wherein n is one to 3;
B is --N(R.sub.4)CH(R.sub.3)C(O)-- wherein R.sub.4 is hydrogen or lower alkyl and R.sub.3 is lower alkyl, cycloalkyl, or cycloalkylalkyl;
C is --N(R.sub.5)CH(R.sub.6)C(O)-- wherein R.sub.5 is hydrogen or lower alkyl and R.sub.6 is hydrogen, lower alkyl, cycloalkyl, or cycloalkylalkyl;
R is lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, or bicyclic heterocyclic;
X is --CH.sub.2 -- or --C(O)--;
D is
(1) --OR.sub.7 wherein R.sub.7 is hydrogen, lower alkyl, cycloalkyl, or cycloalkylalkyl;
(2) --NR.sub.8 R.sub.9 wherein R.sub.8 and R.sub.9 are independently selected from hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, and --(CH.sub.2).sub.m --Z wherein m is two to eight and Z is --OH, heterocyclic, --SO.sub.3 H, --CO.sub.2 R.sub.10 wherein R.sub.10 is hydrogen or lower alkyl or Z is --NR.sub.11 R.sub.12 wherein R.sub.11 and R.sub.12 are independently selected from hydrogen, lower alkyl, cycloalkyl, and cycloalkylalkyl;
(3) --NHCH(R.sub.13)C(O)-- wherein R.sub.13 is hydrogen, lower alkyl, cycloalkyl, or cycloalkylalkyl; or
(4) --NHCH(R.sub.13)C(O)NHCH(R.sub.14)C(O)-- wherein R.sub.13 is hydrogen, lower alkyl, cycloalkyl, or cycloalkylalkyl and R.sub.14 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, cyanoalkyl, carboxyalkyl, or alkoxycarbonylalkyl; and
E is
(1) absent;
(2) --OR.sub.15 wherein R.sub.15 is hydrogen, lower alkyl, cycloalkyl, or cycloalkylalkyl; or
(3) --NR.sub.16 R.sub.17 wherein R.sub.16 and R.sub.17 are independently selected from hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, and --(CH.sub.2).sub.p --Y wherein p is two to eight and Y is --OH, heterocyclic, --SO.sub.3 H, --CO.sub.2 R.sub.18 wherein R.sub.18 is hydrogen or lower alkyl or Y is --NR.sub.19 R.sub.20 wherein R.sub.19 and R.sub.20 are independently selected from hydrogen, lower alkyl, cycloalkyl, and cycloalkylalkyl; or a pharmaceutically acceptable salt, ester, or prodrug thereof; and compounds of the Formula II ##STR3## wherein A is hydrogen, an N-protecting group, R.sub.1 NHCH(R.sub.2)C(O)-- wherein R.sub.1 is H or an N-protecting group and R.sub.2 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, carboxyalkyl, or alkoxycarbonylalkyl; or A is HO.sub.2 C(CH.sub.2).sub.n C(O)-- wherein n is one to 3;
B is --N(R.sub.4)CH(R.sub.3)C(O)-- wherein R.sub.4 is hydrogen or lower alkyl and R.sub.3 is lower alkyl, cycloalkyl, or cycloalkyl-alkyl;
C is --N(R.sub.5)CH(R.sub.6)C(O)-- wherein R.sub.5 is hydrogen or lower alkyl and R.sub.6 is hydrogen, lower alkyl, cycloalkyl, or cycloalkylalkyl;
R is lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, or bicyclic heterocyclic;
P.sub.4 is hydrogen, lower alkyl, or benzyl;
X is --CH.sub.2 -- or --C(O)--;
D is
(1) --OR.sub.7 wherein R.sub.7 is hydrogen, lower alkyl, cycloalkyl, or cycloalkylalkyl;
(2) --NR.sub.8 R.sub.9 wherein R.sub.8 and R.sub.9 are independently selected from hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, and --(CH.sub.2).sub.m --Z wherein m is two to eight and Z is --OH, heterocyclic, --SO.sub.3 H, --CO.sub.2 R.sub.10 wherein R.sub.10 is hydrogen or lower alkyl or Z is --NR.sub.11 R.sub.12 wherein R.sub.11 and R.sub.12 are independently selected from hydrogen, lower alkyl, cycloalkyl, and cycloalkylalkyl;
(3) --NHCH(R.sub.13)C(O)-- wherein R.sub.13 is hydrogen, lower alkyl, cycloalkyl, or cycloalkylalkyl; or
(4) --NHCH(R.sub.13)C(O)NHCH(R.sub.14)C(O)-- wherein R.sub.13 is hydrogen, lower alkyl, cycloalkyl, or cycloalkylalkyl and R.sub.14 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, cyanoalkyl, carboxyalkyl, or alkoxycarbonylalkyl; and
E is
(1) absent;
(2) --OR.sub.15 wherein R.sub.15 is hydrogen, lower alkyl, cycloalkyl, or cycloalkylalkyl; or
(3) --NR.sub.16 R.sub.17 wherein R.sub.16 and R.sub.17 are independently selected from hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, and --(CH.sub.2).sub.p --Y wherein p is two to eight and Y is --OH, heterocyclic, --SO.sub.3 H, --CO.sub.2 R.sub.18 wherein R.sub.18 is hydrogen or lower alkyl or Y is --NR.sub.19 R.sub.20 wherein R.sub.19 and R.sub.20 are independently selected from hydrogen, lower alkyl, cycloalkyl, and cycloalkylalkyl; or a pharmaceutically acceptable salt, ester, or prodrug thereof; and compounds of the Formula III ##STR4## wherein A is hydrogen, an N-protecting group, R.sub.1 NHCH(R.sub.2)C(O)-- wherein R.sub.1 is H or an N-protecting group and R.sub.2 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, carboxyalkyl, or alkoxycarbonylalkyl, or arylalkoxycarbonylalkyl; or A is HO.sub.2 C(CH.sub.2).sub.n C(O)-- wherein n is one to 3; or A is R.sub.1a C(O)-- or R.sub.1a S(O).sub.2 -- wherein R.sub.1a is heterocyclic; or A is (aminoalkyl) (alkyl)aminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, (dialkylaminoalkyl)(alkyl)aminocarbonyl, (aminoalkyl) (alkyl)aminosulfonyl, (alkylaminoalkyl(alkyl)aminosulfonyl, (dialkylaminoalkyl)(alkyl)aminosulfonyl, (heterocyclicalkyl)(alkyl)aminocarbonyl, or (heterocyclicalkyl)(alkyl)aminosulfonyl;
B is --N(R.sub.4)CH(R.sub.3)C(O)-- wherein R.sub.4 is hydrogen or lower alkyl and R.sub.3 is lower alkyl, cycloalkyl, or cycloalkylalkyl;
C is --N(R.sub.5)CH(R.sub.6)C(O)-- wherein R.sub.5 is hydrogen or lower alkyl and R.sub.6 is lower alkyl, cycloalkyl, or cycloalkylalkyl;
R is lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, or bicyclic heterocyclic; and
R.sub.21 is lower alkyl, cycloalkyl, or cycloalkylalkyl; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
European Published Patent Application EP 0518299A2, published Dec. 16, 1992, discloses compounds of Formula I ##STR5## wherein R.sub.1, R.sub.2, and R.sub.3 each represent hydrocarbon groups which may be substituted, except cases in which (1) R.sub.2 is unsubstituted methyl, (2) R.sub.3 is an unsubstituted hydrocarbon group having one to three carbon atoms, and (3) R.sub.1 is benzyloxycarbonylamino-methyl, R.sub.2 is isobutyl, and R.sub.3 is isobutyl or phenylmethyl. The compounds were disclosed as having endothelin converting enzyme inhibiting activity.
Bertenshaw S R, et al, Journal of Medicinal Chemistry 1993;36:173 discloses compounds of the formula ##STR6## wherein X is CH.sub.2, NH, or O;
Japanese Published Patent Application 04327592A, published Nov. 17, 1992, discloses compounds of Formula I ##STR7##
A=leucine, isoleucine, or phenylalanine residue;
Trp=tryptophan residue;
R=lower alkyl, lower alkoxy, or halogen;
X=H or alkali metal;
Y=H, alkali metal, or lower alkyl;
m=0-3;
n=1-4.
R is n-propyl, OEt, Bn, or cyclohexylmethyl as inhibitors of endothelin converting enzyme. The enzyme used in the study was a phosphoramidon sensitive metalloprotease obtained from rabbit lung homogenate.
However, the compounds disclosed in JP 04041430-A, WO 92/12170, WO 92/01468, WO 92/13545, EP 0518299A2, and Journal of Medicinal Chemistry 1993;36:173 do not disclose or suggest the novel hydroxamate peptides of the present invention described hereinafter.